We propose to test the hypothesis that mitochondrial dysfunction is an important factor in the etiology of autism spectrum disorders (ASD). The mitochondria play four central roles in cell and tissue function: they provide most of the energy, generate much of the reactive oxygen species (ROS), buffer cytosolic Ca++, and regulate cell death based on mitochondrial status. The mitochondrial genome is thought to encompass 1500 nuclear DNA (nDNA) genes and 37 mitochondrial DNA (mtDNA) genes. A comparative genomic hybridization (CGH) analysis of ASD lymphoblastoid cell line DNAs has revealed multiple copy number variants (CNVs) that impact nDNA mitochondrial genes, many CNVs being internal to the mitochondrial genes. Additional analyses have revealed mtDNA alterations. Since a partial mitochondrial oxidative phosphorylation (OXPHOS) defect is sufficient to generate neurological disease, these results suggest that mitochondrial dysfunction could account for a significant proportion of ASD. To further test this hypothesis we propose to: (1) expand our search for nDNA CNVs affecting mitochondrial genes in ASD lymphoblastoid cell lines, (2) analyze mtDNA variation in the ASD lymphoblasts, (3) use mitochondrial biochemistry and somatic cell genetics to demonstrate that the lymphoblasts manifest the mitochondrial defect predicted by the nDNA and/or mtDNA variants, and (4) confirm the presence of mitochondrial defects in selected mutant patients using non-invasive magnetic resonance spectroscopy (MRS) of muscle and brain, micro-organic breath analysis (MOBA), and the diffuse optical spectroscopy (DOS) of muscle. Demonstration that a subset of ASD patients harbor mitochondrial defects would suggest new approaches for the treatment of this class of ASD.

Public Health Relevance

To determine if a subset of autism spectrum (ASD) disease is caused by mitochondrial dysfunction, we propose to survey patient lymphoblastoid cell lines for those harboring nuclear DNA (nDNA) copy number variants (CNVs) or mitochondrial DNA (mtDNA) mutations that alter mitochondrial genes. Cell lines from the mutant patients will be tested for the expected mitochondrial function. If mitochondrial defects are found, selected patients will be tested using non-invasive biophysical and biochemical tools to determine if they manifest a functional mitochondrial defect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS070298-02
Application #
7938974
Study Section
Special Emphasis Panel (ZMH1-ERB-B (A1))
Program Officer
Mamounas, Laura
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$657,793
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Potluri, Prasanth; Procaccio, Vincent; Scheffler, Immo E et al. (2016) High throughput gene complementation screening permits identification of a mammalian mitochondrial protein synthesis (?(-)) mutant. Biochim Biophys Acta 1857:1336-1343
Beier, Ulf H; Angelin, Alessia; Akimova, Tatiana et al. (2015) Essential role of mitochondrial energy metabolism in Foxp3? T-regulatory cell function and allograft survival. FASEB J 29:2315-26
Picard, Martin; Zhang, Jiangwen; Hancock, Saege et al. (2014) Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc Natl Acad Sci U S A 111:E4033-42
Golomb, Beatrice A; Erickson, Laura C; Scott-Van Zeeland, Ashley A et al. (2014) Assessing bioenergetic compromise in autism spectrum disorder with 31P magnetic resonance spectroscopy: preliminary report. J Child Neurol 29:187-93
Wallace, Douglas C; Chalkia, Dimitra (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol 5:a021220
Wallace, Douglas C (2013) Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases. Philos Trans R Soc Lond B Biol Sci 368:20120267
Lott, Marie T; Leipzig, Jeremy N; Derbeneva, Olga et al. (2013) mtDNA Variation and Analysis Using Mitomap and Mitomaster. Curr Protoc Bioinformatics 44:1.23.1-26
Wallace, Douglas C; Chalkia, Dimitra (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Med 3:a021220
Wallace, Douglas C (2013) A mitochondrial bioenergetic etiology of disease. J Clin Invest 123:1405-12

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